Field of the Invention
Aspects and embodiments of the present invention relate to the treatment of neurological disorders, for example neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and stroke. Particularly although not exclusively, the present invention relates at least in part to a GIP/GLP1 co-agonist peptide for use in the treatment of such neurological disorders. Also included in the present invention are inter alia pharmaceutical compositions comprising a GIP/GLP1 co-agonist peptide for use in treatment of such disorders, together with methods of treating such disorders as well as other subject matter.
Description of the Related Art
Alzheimer's disease is a chronic neurodegenerative disorder for which there is no cure. Currently prescribed medication only temporarily relieves some of the symptoms. The main hallmarks of the disease are disorientation, loss of memory, loss of neurons and synapses in the brain, the accumulation of beta-amyloid protein in the brain (amyloid plaques), and intracellular aggregation of hyperphosphorylated tau protein (tangles) (LaFerla and Oddo, 2005; Blennow et al., 2006).
Parkinson′ disease is also a chronic neurodegenerative disease for which only delaying medication is available. The main hallmarks are tremor, rigor, and a loss of ability to move, the degeneration of neurons in the basal brain (substantia nigra) and the loss of release of the neurotransmitter, dopamine (Shen, 2010).
Type 2 diabetes (T2DM) has been identified as a risk factor for AD and PD (Hölscher, 2014), indicating that insulin signalling impairment may be a factor in initiating or accelerating the development of AD. Epidemiological studies found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders at a later stage (Luchsinger et al., 2004; Ristow, 2004; Ohara et al., 2011). It was also shown that insulin signalling in the brain is desensitised in AD patients. Recent studies demonstrated that brains of AD patients had increased levels of inactivated phosphorylated insulin receptors and IRS-1 second messengers, which are both indicative of insulin desensitisation (Moloney et al., 2010; Bomfim et al., 2012; Talbot et al., 2012). In PD, insulin signalling was also found to be impaired and linked to disease progression (Morris et al., 2011; Cereda et al., 2012).
Glucagon-like peptide (GLP-1) is an endogenous 31-amino acid peptide incretin hormone (Baggio and Drucker, 2007). GLP-1 receptor stimulation enhances beta-cell proliferation in the pancreas by activating stem cell proliferation, facilitates glucose-dependent insulin secretion and lowers blood glucose in patients with T2DM (Lovshin and Drucker, 2009). Three GLP-1 analogues are currently on the market as a treatment for diabetes, exendin-4 (Byetta®), lixisenatide (Lyxumia®) and liraglutide (SEQ ID No. 10) (Victoza®) (Campbell and Drucker, 2013; Elkinson and Keating, 2013).
Glucose-dependent insulinotropic peptide (GIP), also known as gastric inhibitory polypeptide, is a 42-amino acid incretin hormone which activates pancreatic islets to enhance insulin secretion and to help reduce postprandial hyperglycaemia, similar to GLP-1 (Gault et al., 2003). GIP is a member of the seretin/glucagon family of neuroregulatory polypeptides which also include the growth hormone releasing factor. It is expressed in pancreatic alpha cells, endocrine cells, and also in neurons in the brain (Nyberg et al., 2007; Campbell and Drucker, 2013). GIP has also been shown to promote pancreatic beta-cell growth, differentiation, proliferation and cell survival, documenting its growth-hormone properties (Gault et al., 2003). Therefore, research is on-going to develop GIP as a therapeutic tool for T2DM treatment (Irwin et al., 2006). There are currently no GIP analogues authorised for the treatment of T2D.
Dual agonist peptides which target more than one receptor are being considered for the treatment of T2D. Several GIP/GLP-1 co-agonist peptides are currently in development for the treatment of T2D. However, there are currently no GIP/GLP-1 dual agonists authorised for use to treat T2D.
Recent investigations of the neuroproperties of GLP-1 and GIP have indicated that these peptides may play a role in preventing neurodegenerative hallmarks in several mouse models of Alzheimer's disease (AD) and also in animal models of Parkinson's disease (PD).
Insulin as well as the incretins not only have growth-factor like properties in the brain, but also modulate synaptic activity (Hölscher, 2014). Synapses are the contacts between neurons, and they are important for memory formation and information processing in the brain. Direct injection of GLP-1 or long-lasting GLP-1 analogues into the brain markedly enhanced long-term potentiation of synaptic transmission (LTP) in the hippocampus, a brain area that is involved in memory formation. LTP is considered a cellular correlate of memory formation (Bliss and Collingridge, 1993). The GLP-1 analogue, liraglutide, has been shown to upregulate LTP in the rat brain (McClean et al., 2010).
In addition, GLP-1 analogues were able to prevent the impairment of LTP that was induced by beta-amyloid fragments (Gault and Hölscher, 2008a; McClean et al., 2011; Gengler et al., 2012; Han et al., 2013). This impairment of LTP by amyloid protein may be the mechanism by which amyloid causes memory loss (Cleary et al., 2005). A study testing liraglutide (SEQ ID No. 10) in an APP/PS1 mouse model of AD showed that the drug can prevent the impairment in memory formation and synaptic plasticity, the reduction of total numbers of synapses, normalise stem cell proliferation and neurogenesis in the dentate gyrus, reduce the inflammation response, and furthermore reduce amyloid plaque load in the cortex and total amyloid levels in the brain (McClean et al., 2011). In another study, liraglutide (SEQ ID No. 10) also had protective and regenerative effects in very old transgenic mice, demonstrating that even at an advanced stage of disease progression, memory can be improved and plaque load be reduced to some degree (McClean and Holscher, 2013).
Based on these findings in animal models, a clinical trial of liraglutide (SEQ ID No. 10) in AD patients has started.
Furthermore, one prior art study has investigated the effects of exendin-4 in the 6-hydroxydopamine model of PD. After the lesion was induced, rats were treated with exendin-4 and a protection of motor activity was observed. Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase- and vesicular monoamine transporter 2-positive neurons in the substantia nigra (Bertilsson et al., 2008). In a second study, two rodent models of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of exendin-4. Motor control was much improved in the drug group, and striatal tissue concentrations of dopamine were markedly higher. In addition, exendin-4 reversed the loss of extracellular DA in the striatum (Harkavyi et al., 2008).
Based on these studies, a clinical trial of exendin-4 in PD patients has been initiated. This study reported that in several motor assessments and in a cognitive test patients had improved, and the improvements were maintained even after the drug had been discontinued for 12 months (Aviles-Olmos et al., 2013; Aviles-Olmos et al., 2014).
Studies have also been carried out to determine whether GIP or GIP analogues have an effect in AD. It has been found that GIP analogues can prevent the LTP impairment that beta-amyloid fragments induce on synaptic transmission in the brain (Gault and Hölscher, 2008b). In a GIP receptor-deletion mouse strain, LTP was also impaired, and paired-pulse facilitation was reduced, indicating that the release of synaptic vesicles is reduced (Faivre et al., 2011). The long-lasting GIP analogue D-Ala2-GIP also had neuroprotective effects in an APP/PS1 mouse model of AD. In 12 months old mice, synaptic plasticity in area CA1 of the hippocampus and spatial memory formation was impaired in APP/PS1 mice but was unimpaired in D-Ala2-GIP treated APP/PS1 mice. In addition, the amyloid plaque load was much reduced, showing impressive effects in reducing the main hallmarks of AD (Faivre and Hölscher, 2013b).
In aged 19 month old AD mice, the drug was still able to reverse some of the AD symptoms such as synapse loss (Faivre and Hölscher, 2013a). In a longitudinal study, oxidative stress and the inflammation response in the brain was much reduced in APP/PS1 mice (Duffy and Hölscher, 2013b). This suggests that these analogues have neuroprotective properties in AD and protect synapses from the detrimental effects of beta-amyloid.
There remains a need to identify treatments for neurological disorders such as for example the neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.